Disruption of <i>CLPB</i> is associated with congenital microcephaly, severe encephalopathy and 3-methylglutaconic aciduria
Bibliographic record
Abstract
BACKGROUND: The heterogeneous group of 3-methylglutaconic aciduria disorders includes several inborn errors of metabolism that affect mitochondrial function through poorly understood mechanisms. We describe four newborn siblings, from a consanguineous family, who showed microcephaly, small birth weight, severe encephalopathy and 3-methylglutaconic aciduria. Their neurological examination was characterised by severe hypertonia and the induction of prolonged clonic movements of the four limbs upon minimal tactile stimulation. METHODS AND RESULTS: Using homozygosity mapping and exome sequencing, we identified a homozygous truncating mutation (p.I562Tfs*23) in CLPB segregating with the disease in this family. CLPB codes for a member of the family of ATPases associated with various cellular activities (AAA(+) proteins) whose function remains unknown. We found that CLPB expression is abolished in fibroblasts from the patients. To investigate the function of this gene, we interfered with the translation of the zebrafish clpb orthologue using an antisense morpholino. The clpb morphants showed an abnormal touch-evoked response with increased swim velocity and tail beat frequency. This motor phenotype is reminiscent of that observed in the patients and is suggestive of increased excitability in neuronal circuits. Interestingly, knocking down clpb reduced the number of inhibitory glycinergic interneurons and increased a population of excitatory glutamatergic neurons in the spinal cord. CONCLUSIONS: Altogether, our study suggests that disruption of CLPB causes a novel form of neonatal encephalopathy associated with 3-methylglutaconic aciduria.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".